Biology subjects

Moss, M.

Publications and source records attributed to Moss, M..

4 recordsLinked to original sources

bioRxiv2024

IRF5 mediates adaptive immunity via altered glutamine metabolism, mTORC1 signaling and post-transcriptional regulation following T cell receptor activation

Although dynamic alterations in transcriptional, translational, and metabolic programs have been described in T cells, the factors and pathways guiding these molecular shifts are poorly understood, with recent studies revealing a disassociation between transcriptional responses and protein expression following T cell receptor (TCR) stimulation. Previous studies identified interferon regulatory factor 5 (IRF5) in the transcriptional regulation of cytokines, chemotactic molecules and T effector transcription factors following TCR signaling. In this study, we identified T cell intrinsic IRF5 regulation of mTORC1 activity as a key modulator of CD40L protein expression. We further demonstrated a global shift in T cell metabolism, with alterations in glutamine metabolism accompanied by shifts in T cell populations at the single cell level due to loss of Irf5. T cell conditional Irf5 knockout mice in a murine model of experimental autoimmune encephalomyelitis (EAE) demonstrated protection from clinical disease with conserved defects in mTORC1 activity and glutamine regulation. Together, these findings expand our mechanistic understanding of IRF5 as an intrinsic regulator of T effector function(s) and support the therapeutic targeting of IRF5 in multiple sclerosis. Sentence SummaryFindings provide new insight into the mechanisms by which T cell intrinsic IRF5 regulates the adaptive immune response via modulation of mTORC1 signaling, glutamine metabolism, and protein translation.

immunology↗

bioRxiv2023

Loss of IRF5 increases ribosome biogenesis leading to alterations in mammary gland architecture and metastasis

Despite the progress made in identifying cellular factors and mechanisms that predict progression and metastasis, breast cancer remains the second leading cause of death for women in the US. Using The Cancer Genome Atlas and mouse models of spontaneous and invasive mammary tumorigenesis, we identified that loss of function of interferon regulatory factor 5 (IRF5) is a predictor of metastasis and survival. Histologic analysis of Irf5-/- mammary glands revealed expansion of luminal and myoepithelial cells, loss of organized glandular structure, and altered terminal end budding and migration. RNA-seq and ChIP-seq analyses of primary mammary epithelial cells from Irf5+/+ and Irf5-/-littermate mice revealed IRF5-mediated transcriptional regulation of proteins involved in ribosomal biogenesis. Using an invasive model of breast cancer lacking Irf5, we demonstrate that IRF5 re-expression inhibits tumor growth and metastasis via increased trafficking of tumor infiltrating lymphocytes and altered tumor cell protein synthesis. These findings uncover a new function for IRF5 in the regulation of mammary tumorigenesis and metastasis. HighlightsLoss of IRF5 is a predictor of metastasis and survival in breast cancer. IRF5 contributes to the regulation of ribosome biogenesis in mammary epithelial cells. Loss of IRF5 function in mammary epithelial cells leads to increased protein translation.

cancer biology↗

bioRxiv2020

High mannose N-glycans on red blood cells as phagocytic ligands, mediating both sickle cell anaemia and resistance to malaria

In both sickle cell disease (SCD) and malaria, red blood cells (RBCs) are phagocytosed in the spleen, but receptor-ligand pairs mediating uptake have not been identified. Here, we report that patches of high mannose N-glycans (Man5-9GlcNAc2), expressed on diseased or oxidized RBC surfaces, bind the mannose receptor (CD206) on phagocytes to mediate clearance. Extravascular haemolysis in SCD correlates with high mannose glycan levels on RBCs. Infection of RBCs with Plasmodium falciparum expose surface mannose N-glycans on healthy RBCs, which occurred at significantly higher levels on RBCs from subjects with sickle cell trait compared to those lacking haemoglobin S. The glycans were associated with high molecular weight complexes and protease-resistant, lower molecular weight fragments containing spectrin. Recognition of surface N-linked high mannose glycans, a novel response to cellular stress, is the first molecular mechanism common to both the pathogenesis of SCD and resistance to severe malaria in sickle cell trait.

immunology↗

bioRxiv2018

Dopaminergic and frontal signals for decisions guided by sensory evidence and reward value

Making efficient decisions requires combining present sensory evidence with previous reward values, and learning from the resulting outcome. To establish the underlying neural processes, we trained mice in a task that probed such decisions. Mouse choices conformed to a reinforcement learning model that estimates predicted value (reward value times sensory confidence) and prediction error (outcome minus predicted value). Predicted value was encoded in the pre-outcome activity of prelimbic frontal neurons and midbrain dopamine neurons. Prediction error was encoded in the post-outcome activity of dopamine neurons, which reflected not only reward value but also sensory confidence. Manipulations of these signals spared ongoing choices but profoundly affected subsequent learning. Learning depended on the pre-outcome activity of prelimbic neurons, but not dopamine neurons. Learning also depended on the post-outcome activity of dopamine neurons, but not prelimbic neurons. These results reveal the distinct roles of frontal and dopamine neurons in learning under uncertainty.

neuroscience↗